rs12771333

Positions:

• chr10-19387632-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142308.3(MALRD1):​c.4546G>A​(p.Glu1516Lys) variant causes a missense change. The variant allele was found at a frequency of 0.136 in 1,550,002 control chromosomes in the GnomAD database, including 15,229 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1088 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14141 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20

Genes affected

MALRD1 (HGNC:24331): (MAM and LDL receptor class A domain containing 1) This gene encodes a conserved protein that features multiple MAM (meprin-A5-protein tyrosine phosphatase mu) and LDLR A2 (low density lipoprotein receptor A2) domains. Expression of this gene is enriched in the small intestine and is upregulated during differentiation of a human cell line that exhibits properties of intestinal epithelial cells. The encoded protein has been shown to modulate production of FGF19 in a human intestinal cell line and may regulate bile acid metabolism in the liver. A synergistic interaction between an allele of this gene and the APOE E4 allele is associated with an elevated risk of Alzheimer's disease in human patients. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029085875).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MALRD1	NM_001142308.3	c.4546G>A	p.Glu1516Lys	missense_variant	27/40	ENST00000454679.7	NP_001135780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MALRD1	ENST00000454679.7	c.4546G>A	p.Glu1516Lys	missense_variant	27/40	1	NM_001142308.3	ENSP00000412763.3
MALRD1	ENST00000377266.7	c.2473G>A	p.Glu825Lys	missense_variant	13/25	5		ENSP00000366477.3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17510 AN: 151944 Hom.: 1090 Cov.: 31

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.122 AC: 18251 AN: 149280 Hom.: 1320 AF XY: 0.127 AC XY: 10231 AN XY: 80376

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.0649

Gnomad ASJ exome AF: 0.0956

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.0906

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.139 AC: 193684 AN: 1397940 Hom.: 14141 Cov.: 32 AF XY: 0.140 AC XY: 96337 AN XY: 689498

Gnomad4 AFR exome AF: 0.0741

Gnomad4 AMR exome AF: 0.0681

Gnomad4 ASJ exome AF: 0.0931

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.0981

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.115 AC: 17513 AN: 152062 Hom.: 1088 Cov.: 31 AF XY: 0.113 AC XY: 8431 AN XY: 74326

Gnomad4 AFR AF: 0.0762

Gnomad4 AMR AF: 0.0963

Gnomad4 ASJ AF: 0.0954

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.0951

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.117

Alfa AF: 0.131 Hom.: 1282

Bravo AF: 0.112

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.146 AC: 562

ExAC AF: 0.122 AC: 2478

Asia WGS AF: 0.153 AC: 531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.92	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.28
Sift	Benign	0.61	.;T
Sift4G	Benign	0.067	T;T
Vest4		0.077
ClinPred		0.014	T
GERP RS		3.1
Varity_R		0.070
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12771333; hg19: chr10-19676561; COSMIC: COSV65989015;